Anti-apoptotic effect of quercetin: Intervention in the JNK- and ERK-mediated apoptotic pathways

Background: Bioflavonoid quercetin inhibits hydrogen peroxide (H(2)O(2))-induced apoptosis via intervention in the activator protein 1 (AP-l)-mediated apoptotic pathway. In this report. we investigated molecular events involved in the anti-apoptotic effect of quercetin, focusing especially on its effects on the family of mitogen-activated protein (MAP) kinases. Methods. Cultured mesangial cells were exposed to H(2)O(2), and activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and p38 MAP kinase was evaluated in the presence or absence of quercetin. Using pharmacological and genetic inhibitors, the roles for individual MAP kinases in H(2)O(2)-induced apoptosis were examined. Involvement of ERKs in the induction and activation of AP-1 was also investigated using Northern blot analysis and a reporter assay. Results. Mesangial cells exposed to H(2)O(2) exhibited rapid phosphorylation of JNK, ERKs, and p38 MAP kinase. Quercetin abrogated the activation of all three MAP kinases in response to H(2)O(2). Pretreatment with MAP kinase kinase inhibitor PD098059 or JNK-c-Jun/AP-1 inhibitor curcumin attenuated the H(2)O(2)-induced apoptosis. Ln contrast, the p38 MAP kinase inhibitor SB203580 did not improve the cell survival. Consistently, transfection with dominant negative mutants of ERK1 and ERK2 or a dominant-negative mutant of JNK inhibited H(2)O(2)-induced apoptosis. Transfection with a dominant-negative p38 MAP kinase did not attenuate the apoptotic process. Inhibition of ERKs by PD098059 suppressed induction of c-fos without affecting early induction of c-jun, leading to attenuated activation of AP-I in response to H(2)O(2). Conclusions. These results suggested that (I) activation of JNK and ERKs, but not p38 kinase, is required for the H(2)O(2)-induced apoptosis: and (2) suppression of the JNR-c-Jun/AP-1 pathway and the ERK-c-Fos/AP-1 pathway is involved in the anti-apoptotic effect of quercetin.